2. Academic Validation
  3. Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis

Human DEF6 deficiency underlies an immunodeficiency syndrome with systemic autoimmunity and aberrant CTLA-4 homeostasis

  • Nat Commun. 2019 Jul 15;10(1):3106. doi: 10.1038/s41467-019-10812-x.
Nina K Serwas 1 2 3,  Birgit Hoeger 1 2 4,  Rico C Ardy 1 2,  Sigrun V Stulz 5,  Zhenhua Sui 6,  Nima Memaran 7 8,  Marie Meeths 9 10,  Ana Krolo 1 2,  Özlem Yüce Petronczki 1 2,  Laurène Pfajfer 1 2 11,  Tie Z Hou 12,  Neil Halliday 12,  Elisangela Santos-Valente 2,  Artem Kalinichenko 1 2,  Alan Kennedy 12,  Emily M Mace 13 14,  Malini Mukherjee 13,  Bianca Tesi 10,  Anna Schrempf 2,  Winfried F Pickl 15,  Joanna I Loizou 2,  Renate Kain 16,  Bettina Bidmon-Fliegenschnee 7,  Jean-Nicolas Schickel 17,  Salomé Glauzy 17,  Jakob Huemer 1 2,  Wojciech Garncarz 1 2,  Elisabeth Salzer 1 2,  Iro Pierides 1 2,  Ivan Bilic 2 18,  Jens Thiel 19,  Peter Priftakis 20,  Pinaki P Banerjee 13 21,  Elisabeth Förster-Waldl 22,  David Medgyesi 1 2,  Wolf-Dietrich Huber 7,  Jordan S Orange 13 14,  Eric Meffre 17,  David M Sansom 12,  Yenan T Bryceson 5,  Amnon Altman 6,  Kaan Boztug 23 24 25 26 27
Affiliations

Affiliations

  • 1 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
  • 2 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 3 Department of Pathology, University of California San Francisco, San Francisco, CA, USA.
  • 4 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria.
  • 5 Centre for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
  • 6 Division of Cell Biology, La Jolla Institute for Allergy & Immunology, La Jolla, CA, 92037, USA.
  • 7 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
  • 8 Centre for Paediatrics and Adoloscent Medicine, Hannover Medical School, Hannover, Germany.
  • 9 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
  • 10 Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
  • 11 Center for Pathophysiology of Toulouse Purpan, INSERM UMR1043, CNRS UMR5282, Paul Sabatier University, Toulouse, France.
  • 12 Institute of Immunity and Transplantation, Division of Infection & Immunity, School of Life and Medical Sciences, University College London, Royal Free Hospital, Rowland Hill Street, London, NW3 2PF, UK.
  • 13 Department of Pediatrics, Baylor College of Medicine and Center for Human Immunobiology, Texas Children's Hospital, Houston, TX, 77030, USA.
  • 14 Columbia University Medical Center, Columbia, NY, USA.
  • 15 Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
  • 16 Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
  • 17 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06511, USA.
  • 18 Takeda (Shire), Vienna, Austria.
  • 19 Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Freiburg, 79106, Germany.
  • 20 Astrid Lindgren Children's Hospital, Karolinska University Hospital Huddinge, Stockholm, Sweden.
  • 21 MD Anderson Cancer Center, Houston, TX, USA.
  • 22 Department of Pediatrics and Adolescent Medicine, Division of Neonatology, Pediatric Intensive Care and Neuropediatrics, Medical University of Vienna, Vienna, Austria.
  • 23 Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria. [email protected].
  • 24 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. [email protected].
  • 25 St. Anna Children's Cancer Research Institute (CCRI), Vienna, Austria. [email protected].
  • 26 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. [email protected].
  • 27 St. Anna Kinderspital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria. [email protected].
PMID: 31308374 DOI: 10.1038/s41467-019-10812-x
Abstract

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or Cancer therapy.

Figures